Delivery System Targets Cancer Metastasis

When it comes to certain types of cancer, the problem is not so much the tumor as it is the spread of cancer to other parts of the body. But now researchers are reporting a new way to inhibit this process.

By delivering an existing anticancer drug in a new way, researchers were able to slow down the spread of cancer in mice without causing chemotherapy–associated side effects. The findings were published in the July 8 issue of the Proceedings of the National Academy of Sciences. (Murphy EA, Majeti BK, Barnes LA, et al. Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis. Proc Natl Acad Sci USA. 2008;105(27):9343-9348.)

Nanotechnology
The team encapsulated the chemotherapy drug doxorubicin (Dox) within a nanoparticle for targeted delivery to a protein marker called anb3, which is found on the surface of certain tumor blood vessels and is associated with blood vessel and tumor growth. The goal was to target the blood vessels around the tumor that cause the spread of cancer, also known as metastasis.

The researchers tested the delivery method in mice implanted with pancreatic tumors. Eleven days after being injected with the anb3-targeted nanoparticle, mice showed about 80% less metastasis to lymph nodes than did mice given the Dox-carrying nanoparticles that didn't attach to anb3 receptors.

The anb3-targeted nanoparticles also shrank the primary tumor by about 23% compared to the control treatment, whereas the non-targeted nanoparticles did not inhibit primary tumor growth. This showed ''that targeting integrin anb3 was necessary for localized tumor cell apoptosis,'' the researchers wrote.

Lead researcher David Cheresh, PhD, associate director for translational research at the Moores Cancer Center at the University of California, San Diego, says he and his colleagues were surprised to see a greater impact on metastasis.

''Primary tumors are not what you typically die from; they are normally removed surgically,'' says Dr. Cheresh. ''It's metastatic disease that kills you. This [drug] would be given in post initial therapy as a prolonged follow-up, a sort of active therapy.''
The nanoparticle was composed of the following fat-related compounds: distearoyl- phosphatidylcholine (DSPC) cholesterol, dioleoylphosphatidylethanolamine (DOPE), distearoylphsphatidylethano-lamine (m-PEG2000-DSPE), and DSPE-cyclic RGDfK.

Lower Dosage
The researchers also sought to determine how much of the unencapsulated chemo-therapy drug would be needed to achieve the same effect as that produced by the anb3-targeted version. ''Fifteen [milligrams per kilogram] is what would be given typically to achieve the anticancer effect,'' Dr. Cheresh says. ''The problem is that's a dose that's very toxic; it causes lots of weight loss and associated side effects. We were able achieve a very effective dose at one kilogram per milligram.''
In fact, dosing the animals with 15 mg/kg caused an 18% reduction in body weight, whereas 1 mg/kg caused a 0.8% reduction in body weight.

According to the study authors, targeted nanoparticle delivery is also an option for newer pharmacological agents designed to suppress tumor or vascular cell signal transduction. This delivery method would likely reduce the dosage of the drug needed for efficacy, thereby minimizing the drug's side effects, they wrote.

Dr. Cheresh says the team is seeking funding to perform additional studies in order to bring the drug to clinical development.